Renal mechanisms of association between fibroblast growth factor 1 and blood pressure

Abstract

The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney andmay contribute to hypertension. However, thebiologicmechanismsunderlying theassociationbetweenFGF1andBPregulation remain unknown.We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65×10-5) and diastolic BP (P=7.61×10-3) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0×10-3). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified126FGF1 partnermRNAs, of which 71 and 63 showedat least nominal associationwith systolic anddiastolicBP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriureticpeptides.Thesefindings indicate thatFGF1 expressionin the kidney is at least under partialgenetic control andthat renal expressionof severalFGF1partnergenes involvedinthenatriuretic peptidecatabolismpathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.